1. Field of the Invention
This invention relates to a product and process for controlling the transfer of passive immunity to newborn domestic animals such as calves, and more particularly, to the use of ultrafiltration techniques or combined ultrafiltration and ion exchange techniques to extract immunoglobulin molecules from lactoserum such as whey to produce a highly concentrated immunologically active product which can be fed to newborn animals under controlled conditions to achieve passive immunity.
2. Description of the Prior Art
As is common with most domestic animals, bovine calves are born without immunity. Passive immunity is transferred on a postpartum basis from a dam (mother) to the newborn calf through an initial mammary gland secretion known as colostrum. As illustrated by FIG. 1, this initial colostrum secretion contains rapidly diminishing levels of immunologically active, large molecular weight proteins known as immunoglobulins (abbreviated below as "Ig"). These Ig molecules possess antibody properties, are actively produced by mature animals, and enhance immunity to infection by bacteria, viruses or parasites. At birth, a calf lacks Ig in its blood serum. Only as a direct response to ingestion and absorption of a quantity and quality of Ig from maternal colostrum shortly after birth can a calf's immune system function efficiently.
The first essential element of the natural passive immunity transfer mechanism relates to the characteristics of the maternal colostrum. To achieve ideal passive immunity, the maternal colostrum should contain an adequate concentration of Ig having an appropriate distribution of pathogen specific antibodies and an appropriate concentration of each pathogen specific antibody. If the maternal colostrum contains an insufficient concentration of important pathogen specific antibodies, the calf will absorb an insufficient quantity of these antibodies and will develop a deficient level of immunity to the diseases which such antibodies attack.
The second essential element of the natural passive immunity transfer mechanism is calf-oriented and relates to the quantity and time of colostrum ingestion. As to quantity of ingestion, previous studies have indicated that there is a limit to the volume of colostrum that can be ingested to maximize the level of Ig absorbed into the calf's circulatory system. Consumption of more than two liters of colostrum fails to enhance calf Ig absorption levels to any significant degree. Furthermore, newborn calves rarely ingest more than two liters of liquid within a feeding period. As to the time of ingestion, FIG. 2 illustrates that the permeability of the newborn calf's gut to the large molecular weight Ig molecules diminishes very rapidly after birth as a result of intestinal cell maturation. This well-known natural intestinal mechanism may be referred to as the "critical period of absorption" which defines the short postpartum interval during which the calf must consume and absorb the optimum quantity of ideal potency colostrum to achieve an ideal level of passive immunity. Although colostrum consumption as late as twenty-four hours postpartum may achieve some immune transfer, subsequent colostrum consumption will have very little effect on passive immune levels. Ideally, colostrum ingestion should occur within the first eight hours postpartum.
In practice, a high percentage of calves either consume far less than an ideal quantity and quality of colostrum or fail to consume colostrum within the critical absorption period. The resulting adverse effects due to the lack of immune transfer are demonstrated by high calf death rates, increased susceptibility to disease and reduced growth rate.
FIG. 3 charts calf blood serum Ig concentration versus time to illustrate the passive immunity transfer mechanism described above under absolutely ideal conditions which rarely occur in nature. At birth, a calf lacks immunity to disease as is demonstrated by the low blood serum antibody concentration. Within approximately six to twelve hours after birth as indicated by reference number 1, the calf ingests two liters of colostrum having an ideal Ig concentration and distribution of pathogen specific antibodies. As these large molecular weight Ig or antibody molecules are intestinally absorbed, the blood serum antibody concentration rapidly increases as indicated by the upwardly sloping line designated by reference number 2. At the time several hours after initial colostrum ingestion designated by reference number 3, the transfer of colostrum Ig molecules from the gut into the calf's bloodstream has been completed. Over the next few days, the blood serum Ig concentration derived from the maternal colostrum gradually declines through normal systemic turnover. Following the time indicated by reference number 4, the calf's immune system commences active Ig production which replaces the declining supply of colostrum-derived Ig. By the time indicated by reference number 5, the calf's immune system achieves a self-sustaining or active Ig production and will maintain an essentially constant blood serum Ig concentration.
Previous research has indicated that a blood serum Ig concentration on the order of twenty milligrams per milliliter or above is highly desirable. Calves possessing such Ig concentrations demonstrate a markedly reduced mortality rate, a high level of resistance to disease and impressively enhance growth rates in comparison to calves having lower levels of passive immunity.
The dramatic contrast between an ideal immunity transfer as illustrated in FIG. 3 and common naturally occuring immunity transfer is illustrated in FIG. 4. Consumption of an insufficient quantity of colostrum or consumption of low Ig concentration colostrum as described in the following paragraph produces a passive immunity transfer curve analogous to that designated by reference number 6 in FIG. 4. If a calf having this deficient level of passive immunity is exposed to a disease, there is a high probability that it will contract the disease, require expensive medical treatment and may die or lack sufficient growth potential.
Because domestic dairy cattle have been selectively bred for maximum milk production, the passive immunity transfer problems encountered by dairymen are particularly acute. At the onset of lactation, a dairy cow's high milk production volume rapidly dilutes the limited quantity of colostrum Ig molecules. As a result, the concentration of these Ig molecules in the fluid initially consumed by a newborn calf may be far below the level required to achieve an adequate level of passive immunity. Since the typical non-aggressive dairy calf consumes only a comparatively small amount of colostrum during the critical absorption period, the number of Ig molecules present in the calf's gut and available for absorption into the bloodstream is frequently unacceptably low. The resulting passive immunity level fails to provide adequate disease resistance.
To combat the immunity deficiency problems outlined above, some dairymen having small dairy herds manually milk what they believe to be an adequate quantity of colostrum from a dam and force feed it to its newborn calf during the critical absorption period. This labor intensive method of controlling the timing and quantity of colostrum consumption cannot compensate for colostrum having a low Ig concentration or an inadequate spectrum of pathogen specific antibodies. Since only complex, time consuming laboratory tests can measure the colostrum Ig concentration and antibody distribution, these dairymen have no way of verifying that the colostrum which they laboriously obtain and force feed to newborn calves will provide adequate levels of passive immunity.
In large dairy operations, a different tactic has been implemented in an attempt to control the time of colostrum ingestion, the quantity of Ig consumed and the pathogen specific antibody distribution of the colostrum. Milk drawn from a group of dams within twelve hours postpartum is blended together. An appropriate quantity of this blended "colostrum" is fed to each newborn calf. Because dairymen have no way of controlling the Ig concentration or distribution of pathogen specific antibodies in this blended "colostrum," this labor intensive procedure has not achieved satisfactory results.
Another existing technique for enhancing the disease resistance of a calf to a specific disease involves prepartum vaccination of the dam. The vaccination increases the serum blood level concentration of the desired pathogen specific antibody and ultimately yields colostrum having enhanced levels of the desired antibody. After consuming this enhanced colostrum, the calf attains an increased level of immunity, but only to the selected disease. Besides the obvious risk to the dam, vaccination procedures are time critical and expensive.
In laboratory studies, researchers have assayed the Ig concentration and distribution of pathogen specific antibodies in colostrum and have administered controlled quantities of such assayed colostrum to newborn calves at controlled times within the critical absorption period. A direct correlation between these measured colostrum Ig variables and calf disease resistance, death rate, and growth rate has been demonstrated. Although these laboratory testing activities have substantially increased the level of knowledge of the natural passive immunity transfer mechanism in animals, they have not solved the immunity transfer problems outlined above by providing a method for positively controlling the Ig concentration and distribution of pathogen specific antibodies in colostrum.
The substantial economic loss suffered by dairymen and others as a direct result of the inability to control the passive immunity transfer mechanism, even in view of a complete comprehension of the operation of that natural mechanism, evidences a strong need for a product or process capable of positively controlling the immunity transfer mechanism. In an attempt to satisfy this need, a genetic engineering firm has recently introduced an artificially synthesized Ig molecule which includes a single antibody pathogen specific to enterotoxigenic E. coli, a bacterium which induces a diarrhea condition in calves known as scours. Scours commonly affects newborn calves and lead to rapid, uncontrollable dehydration and frequent death. This synthesized product is administered orally within twelve hours postpartum and is capable of producing increased immunity only to that specific E. coli bacterium.
It is therefore a major object of the present invention to provide a process for extracting naturally occurring Ig molecules from milk or whey to produce a highly concentrated immunologically active product which can subsequently be dissolved in a fluid to produce a colostrum substitute or supplement having a controlled Ig concentration and a known distribution and concentration of numerous desirable pathogen specific antibodies.
It is another major object of the present invention to provide a process for controlling the natural passive immunity transfer mechanism by feeding a controlled quantity of the whey-derived product to newborn animals within the critical absorption period to achieve a designated blood serum concentration of each of a broad spectrum of identified pathogen specific antibodies to provide enhanced levels of passive immunity to selected diseases without reliance on consumption of natural colostrum.
Another major object of the present invention is to derive said product from whey, a low economic value dairy manufacturing byproduct.
Another object of the present invention is to provide a process for producing said whey-filtered product by using commercially available equipment common in dairy manufacturing plants.
Another object of the present invention is to provide a process for producing said whey-derived product in large quantities at an affordable, cost effective price.
Another object of the present invention is to provide said whey-derived product in a dry powder form which can be stored for a substantial period of time.
Another object of the present invention is to provide a process for producing said product from milk obtained from a group of animals having an enhanced level of immunity to a specific disease and feeding said product to calves born into another herd which requires an enhanced level of immunity to that same disease.
It is still another object of the present invention to provide said whey-derived product which can be administered to a newborn calf in a quantity directly related to the calf's needs, according to size, to provide passive immunity.
Briefly stated, the present invention encompasses a process for extracting immunologically active immunoglobulins from milk. The milk is initially processed into whey. Ultrafiltration of the whey produces a retentate having an increased concentration of immunoglobulins. The residual liquid components are removed from the ultrafiltration retentate to produce a filtered product having a further increased concentration of immunoglobulins. Each step in the process is executed under conditions which substantially maintain the immunological activity of the immunoglobulins. The filtered product is subsequently dissolved in a liquid such as colostrum, milk or water to achieve a desired Ig concentration. This Ig solution is ingested by a newborn domestic animal such as a calf postpartum within the critical absorption period. Ion exchange techniques may be implemented to further process an ultrafiltration retentate to significantly increase the concentration of immunologically active Ig in the whey-derived product. This higher concentration Ig product may be blended with a relatively lower Ig concentration filtered product to yield a product having a substantially increased Ig concentration in comparison to Ig concentration levels attainable through use of ultrafiltration alone.
By implementing the process of the present invention, passive immunity can be transferred to a newborn domestic animal under controlled conditions, ensuring an adequate level of passive immunity to a broad spectrum of disease.